Myc is an oncoprotein transcription factor that features prominently in a variety of human cancers. Indeed, it is estimated that approximately one-third of all cancer deaths in the United States involve inappropriate Myc expression or activity. Cells have evolved a number of mechanisms to restrict Myc expression in normal cells, one of which is ubiquitin (Ub)-mediated proteolysis. The importance of Myc destruction is evidenced by the fact that cancer-associated mutations within Myc block its destruction and potently enhance its oncogenic activity. The goal of this proposal is to understand the mechanisms and consequences of the destruction of Myc by the Ub-proteasome system. Four Specific Aims are proposed. Aim 1 will investigate the mechanisms through which Myc stability is regulated. Much of this analysis will focus on the identification and characterization of proteins that interact with a central element within Myc that is important for its post- ubiquitylation destruction. Aim 2 is focused on understanding how the adenoviral oncoprotein E1A stabilizes Myc, and the contribution of this activity to E1A's oncogenic capabilities. In Aim 3, the emphasis will shift to analysis of a highly-conserved, but little-studied, element in Myc that is important for Myc turnover and contributes to oncogenic transformation by dampening the ability of Myc to induce apoptosis. Finally, in Aim 4, the activity of a number of tumor-derived, stable, Myc mutants will be studied in detail to learn the mechanisms though which Myc function is perturbed in cancer. These studies make extensive use of cell based assays, RNAi, microarray experiments, proteomic analyses, as well as cutting-edge mouse models of lymphomagenesis, hepatocellular carcinoma, and breast cancer. Because the Ub-proteasome system is emerging as an attractive target for anti-tumor therapies, understanding how and why Myc is destroyed offers the potential to reveal new strategies for treating human cancer.